Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas

Abstract

Temozolomide is effective in some patients with progressive pituitary adenoma or carcinoma. We report a survey study of Italian patients treated with Temozolomide because of aggressive pituitary adenoma or carcinoma resistant to standard therapies. Italian endocrinologists were surveyed and asked to participate into the study. A questionnaire was sent to all those who agreed and had used Temozolomide in at least one patient with pituitary tumor. Database was closed in December 2013. A literature review was also performed. Thirty-one patients were included into the analysis. Mean age at start of Temozolomide treatment was 58.3 ± 1.9 years (± standard error). Six of the 31 (19.4%) Italian patients had a pituitary carcinoma. Twenty-five patients (80.6%) had disease control during Temozolomide treatment, while 6 patients (19.4%) had disease progression. Median follow-up after beginning Temozolomide was 43 months. Thirteen patients had tumor growth after stopping Temozolomide. The 2-year progression-free survival was 47.7% (95% CI 29.5-65.9%), while the 2-year disease control duration was 59.1% (95% CI 39.1-79.1%). Eleven patients died of progressive disease and other two patients of unrelated causes. The 2-year and 4-year overall survival rates were 83.9% (95% CI 70.7-97.1%) and 59.6% (95% CI 40.0-79.2%), respectively. Temozolomide is an additional effective therapeutic option for the treatment of aggressive pituitary tumors. The drug is well tolerated and causes few severe adverse effects. Recurrence of the tumor can occur after an initial positive response and usually portends a grim outcome.

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

“…In a series of 24 patients (25), adverse effects were reported in 54% of the patients. Most were mild, similar to a report of 31 patients (12), and in a review of the 40 earliest published cases (111). Nausea/vomiting occurred in around onethird of temozolomide-treated patients consistently across studies of pituitary and other tumours (111,112).…”

“…In another eight patients with Nelson's syndrome, pasireotide had minimal effects on tumour volume, in spite of reductions in ACTH levels in most patients (Daniel et al, abstract Endo 2016, OR 18-5). In a recent report on three patients with aggressive atypical corticotroph macroadenomas, of which one was a carcinoma, pasireotide was not clinically useful (95), and in three patients with recurrent corticotroph tumour after discontinuation of TMZ, pasireotide had no effect (12). There are several reports of corticotroph tumour growth after bilateral adrenalectomy, as well after achieving eucortisolism after treatment with steroidogenic inhibitors (96).…”

“…Methylguanine methyltransferase (MGMT) levels were measured in 3 of the 4 patients, and were low in these three patients, which possibly contributed to the outcome (see 'Predictors of response to temozolomide' section). Others have added capecitabine to TMZ after TMZ failure, or at progression after an initial response to TMZ alone, but had not observed an enhanced effect (11,12,25,107).…”

“…Importantly, myelosuppression was reported in 31% of the patients (25). Frequently, a dose reduction (Supplementary Table 7) or delay in treatment cycles can allow the patient to continue treatment (12,25).…”

“…Early identification of aggressive pituitary tumours is challenging, but is of major clinical importance as they are associated with an increased morbidity and mortality even in the absence of metastases (11,12). Despite numerous studies and advances in prognostic classification, no pathological marker has been shown as yet to reliably predict pituitary tumour behaviour (6,13,14,15).…”